Neurofibrillary pathology is a common feature of a large number of neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). Although several proteins are disrupted in the pathogenic pathway leading to tangle formation, the microtubule binding protein tau is of significant interest as it is a major component of tangles in the AD brain, and mutations in tau can cause neurodegenerative diseases such as frontal temporal lobe dementia. Understanding how tau becomes pathogenic, and how pathogenic tau disrupts the normal functioning of the neuron ultimately leading to its death are the overall goals of this program. To address these questions, we have taken a multidisciplinary approach. Project 1 will examine gene profiles in single neurons with and without neurofibrillary pathology at different stages to identify what pathways are affected during the disease process. Project 2 will look at the turnover and transport of tau. Project 3 will look at the effect of tauopathy on neuronal integrity using in vivo imaging and project 4 will further put these observations into functional context by examining how pathogenic tau formation impacts system integrity. Project 5 will examine the contribution of phosphorylation or aggregation to the pathogenic process, and will test therapeutic agents that target these systems, as well as explore the role of Abeta in tangle formation, and the use of an Abeta targeting agent to reduce both the amyloid and tangle pathologies of AD. The program will mainly use a new mouse model, the hTau line, that has progressive tauopathy of great relevance to AD. The distribution of this model to program participants will be facilitated by the use of a mouse husbandy core, and coordination of effort and feedback from advisory groups will be facilitated by the use of an administrative core. The individual projects and collective expertise of the program participants will synergize to generate a well-controlled wealth of information about how, and why pathogenic tau forms, and the functional impact of tauopathy at different stages of disease progression. This information, coupled with the judicious use of relevant proof-of concept therapeutic candidates will also begin to address issues of how best to start treating tauopathies such as AD.